PD-L1 underexpression

While the correlation between treatment effects on PFS and OS was weak in ESCC, it was moderate in PD-L1-low GEA, and good in PD-L1-high GEA. Therefore, PFS is an adequate co-primary endpoint in future trials investigating novel ICIs-based regimens in GEA, especially if the analyses are pre-planned in PD-L1-high subgroups.

PD-L1 expression defines a biologically and clinically relevant subset of ATCs with distinct immune features and therapeutic vulnerabilities. Standardizing PD-L1 testing and integrating it with molecular and microenvironmental biomarkers will be essential to refine patient selection for immunotherapy and combination strategies, improving outcomes.

These findings suggest that LKB1 loss suppresses DPP4 expression, contributing to the immunosuppressive characteristics of the TME in KL-NSCLC cells, whereas restoring DPP4 expression promotes NK cell recruitment, facilitates immune activation, and enhances the effects of anti-PD-1 therapy. These results suggest that DPP4 is a key immune modulator and a promising therapeutic target, providing a novel strategy to overcome immune resistance and improve immunotherapy outcomes in this challenging subset of lung cancer.

In first-line chemoimmunotherapy-treated PD-L1-low/negative NSCLC, baseline LIPI can be used to independently stratify PFS and OS and identify a subgroup with poor prognosis. LIPI may support risk stratification at first-line treatment initiation. Prospective studies are warranted to validate these findings and optimize personalized treatment approaches.

KIF20A drives primary anti-PD-1 resistance in NSCLC through PD-L1 suppression and independently predicts poor survival. The KIF20A/PD-L1 signature stratifies patient risk, positioning KIF20A as both a prognostic biomarker and a therapeutic target to overcome immunotherapy resistance.

LCT enhances survival in mNSCLC with ORD post-immunotherapy, irrespective of PD-L1 status. These findings support integrating LCT into standard care for immunotherapy-responsive ORD populations.

Based on sensitivity analysis of chemotherapeutic agents, we found the highest positive correlation between SLC11A1 and "BI.2536" and the strongest passive correlation of HCLS1 and GBP2 with "Ribociclib", as well as P2RX7 with "BMS.754807". Quantitative real-time polymerase chain reaction suggested that the expression trends of GBP2, P2RX7, and HCLS1 were consistent with the results of bioinformatic analysis. Regulated cell death-related genes (GBP2, SLC11A1, P2RX7, and HCLS1) may play a role in endometrial carcinoma development, which can provide new ideas for the treatment and prognosis prediction of this disease.

Tumor-associated Akk may serve as a negative predictive biomarker for ICI efficacy in NSCLC patients with low PD-L1 expression. Our findings suggest that tumor microbiota profiling, particularly targeting Akk, could refine patient stratification and therapeutic decision-making.

In vivo treatment experiments demonstrated that anti-BTLA immunotherapy reinvigorated antitumor immunity in TME, resulting in enhanced tumor inhibition and survival improvement in FXRhiPD-L1lo mouse Lewis lung carcinomas. In summary, our findings establish the FXR/HVEM axis as an immune evasion mechanism in PD-L1lo/- NSCLC, providing translational implications for future immunotherapy in this subgroup of patients.

To the best of our knowledge, this is the first documentation demonstrating that atezolizumab is transported to CD63-positive organelles, thereby enhancing our understanding of its intracellular trafficking. Our study also strengthens the concept of PIT and atezolizumab-based targeting of PD-L1+ NSCLCs.

Finally, the 12-month follow-up of blood biomarkers revealed no change in the receptors, except for CTLA-4. The results of the present study suggested that immune exhaustion, defined as increased expression of exhaustion receptors in lymphocytes, was not present in tissues from patients with ccRCC with localized disease.

Chemotherapy appears to upregulate IDO and PD-L1 expressions in TSCC, highlighting the potential for integrating immunotherapy into treatment regimens. Further studies are needed to explore the dynamics of these biomarkers over time and their impact on patient outcomes, emphasizing the need for comprehensive therapeutic strategies.